January 4, 2005

Penn Researchers Find that Residual Tumor Cells are a Barrier to Targeted Cancer Therapeutics

(Philadelphia, PA) – Over the past five years, so-called molecularly targeted therapies for cancer have held out great promise. These therapies are based on blocking a cancer-causing genetic pathway that has been turned on in a tumor, thereby allowing it to proliferate and grow in an uncontrolled manner. For a small number of cancers, chronic treatment with molecularly targeted therapies has been shown to be effective in the clinic – at least in the short-term. Recently, based on animal models, several investigators have proposed that chronic treatment – possibly even brief treatment – with molecularly targeted therapies might eliminate cancers. Curing cancers with short-term treatment, however, contrasts sharply with clinical experience with cancer patients, say Penn researchers. This suggests that tumors often become resistant to therapy by finding a way around the genetic blockade.

Using a model for breast cancer, researchers in the Abramson Family Cancer Research Institute of the University of Pennsylvania report that after blocking the gene c-MYC, which is commonly overexpressed in human breast cancers, the tumor still persists. Senior author Lewis A. Chodosh, MD, PhD, Associate Professor, Departments of Cancer Biology and Medicine, and colleagues report their findings in the December issue of Cancer Cell.

Specifically, the group found that after turning off c-MYC in a mouse model, 50 percent of c-MYC-induced mammary cancers were still able to grow. They also found that residual cancer cells persisted in all animals – even those that were seemingly cancer-free. These residual cells quickly recovered their malignant properties either spontaneously or after the researchers reactivated MYC. Additionally, by sequentially turning the MYC gene on and off in these tumors in order to simulate the treatment of patients with multiple rounds of a molecularly targeted therapy, the investigators found that nearly every tumor eventually progressed to a state that was no longer dependent upon MYC for growth.

With these experiments, Chodosh and colleagues demonstrated that small numbers of breast cancer cells that remain following targeted therapy provide a means for cancers to escape and eventually recur. When tumors shrink in response to therapy, they leave residual cells that ultimately give rise to recurrences. Furthermore, if the targeted oncogene becomes reactivated in those cells, they grow into full-blown tumors very quickly. “Any way you look at it, when physicians apply a selective pressure to a tumor by blocking an oncogenic pathway, cells escape,” says Chodosh. “They find a back door and progress to a more aggressive state that becomes independent of that pathway.”

Chodosh concludes that the type of genetically engineered mouse models used in these MYC studies yield results that are very similar to what is observed in patients and that molecular therapies will likely need to be applied chronically to prevent the regrowth of residual tumor cells that remain after therapy. He further emphasizes that molecularly targeted therapies will need to be combined with agents that target secondary pathways of tumor escape in order to achieve lasting cures.

Penn colleagues on this study are: Robert B. Boxer, Joanne W. Jang, and Louis Sintasath. This work was funded the National Cancer Institute, the US Army Breast Cancer Research Program, and the Susan G. Komen Breast Cancer Foundation.

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The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation’s best in cancer care, according to U.S. News & World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment.

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System is comprised of: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.

This release is available online at http://www.uphs.upenn.edu/news/News_Releases/jan05/cMYCgeneblocking.htm